Regorafenib + Immunotherapy for Colorectal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Regorafenib, Anti-PD-1, CTLA-4

Disqualifiers: MSI-H colorectal cancer, Autoimmune disease, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

39 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of regorafenib when given together with ipilimumab and nivolumab in treating patients with microsatellite stable colorectal cancer that has spread to other places in the body (metastatic) and remains despite chemotherapy treatment (resistant). Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving regorafenib, ipilimumab and nivolumab may slow the tumor growth and/or shrink the tumor size in patients with colorectal cancer.

Will I have to stop taking my current medications?

The trial requires that you have not had systemic anti-cancer treatment within 14 days or less than 5 half-lives of the first dose of the study treatment. If you are on corticosteroids or other immunosuppressive medications, you must stop them 14 days before starting the study treatment, unless they are inhaled, topical, or low-dose adrenal replacement steroids.

What data supports the effectiveness of the drug Regorafenib in combination with immunotherapy for colorectal cancer?

Research shows that Regorafenib, when used alone, has been effective in extending survival in patients with metastatic colorectal cancer who have tried other treatments. Additionally, early studies suggest that combining Regorafenib with immunotherapy drugs like Nivolumab may enhance its antitumor activity in colorectal cancer. ^{1 2 3 4 5}

What safety information is available for Regorafenib and Immunotherapy in humans?

Immune checkpoint inhibitors like Ipilimumab and Nivolumab can cause immune-related side effects, including colitis (inflammation of the colon) and other serious conditions. These side effects can sometimes be severe, requiring treatment with steroids or other medications. It's important for patients to be closely monitored for these adverse effects during treatment. ^{6 7 8 9 10}

How is the drug combination of Regorafenib, Ipilimumab, and Nivolumab unique for treating colorectal cancer?

This drug combination is unique because it combines Regorafenib, a multi-kinase inhibitor that targets cancer growth pathways, with Ipilimumab and Nivolumab, which are immunotherapies that help the immune system attack cancer cells. This approach is novel as it integrates targeted therapy with immunotherapy, potentially offering a new option for patients with colorectal cancer who have not responded to standard treatments. ^{1 2 3 5 11}

Research Team

Marwan G Fakih

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer that's stable at the microsatellite level and hasn't responded to chemotherapy. Participants should have a good performance status, acceptable organ function tests, measurable disease, and no prior treatment with the study drugs. They must not be pregnant or breastfeeding and agree to use contraception.

Inclusion Criteria

Anticipated life expectancy greater than 3 months

My liver enzymes are within the allowed range for my cancer condition.

My colorectal cancer is not microsatellite unstable.

Exclusion Criteria

I had cancer before, but it's not skin cancer or certain in situ cancers, and I'm not currently undergoing treatment.

Pregnancy or breast feeding

I have brain metastases but am stable, not on high steroids, or my steroid dose is stable or decreasing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive regorafenib orally once daily on days 1-21, nivolumab intravenously every 2 weeks, and ipilimumab intravenously every 6 weeks. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 and 90 days, then every 3 months for up to 5 years.

5 years

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Regorafenib

Trial Overview The trial is testing the combination of Regorafenib (a growth inhibitor), Ipilimumab, and Nivolumab (both immune system boosters) in patients whose colorectal cancer has spread and resisted chemotherapy. It aims to find the safest dose while observing how well these drugs work together against cancer.

Participant Groups

Group I: Treatment (regorafenib, nivolumab, ipilimumab) Experimental Treatment 3 Interventions

Patients receive regorafenib PO QD on days 1-21, nivolumab IV over 30 minutes Q2W, and ipilimumab IV over 30 minutes Q6W. Cycles repeat every 28 day for up to 2 years in the absence of disease progression or unacceptable toxicity.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 72 patients with microsatellite stable metastatic colorectal cancer, regorafenib or fruquintinib combined with sintilimab showed a median progression-free survival of 4.2 months and an overall survival of 10.5 months, indicating these combinations are viable third-line treatment options.

The treatment was generally well-tolerated, with only 15.3% of patients experiencing severe adverse events, and patients without liver metastasis showed better response rates and overall survival, suggesting they may benefit more from this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. Nie, C., Lv, H., Chen, B., et al.[2022]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Regorafenib significantly improves median overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer (mCRC), as shown in the CORRECT trial with a regimen of 160 mg daily for 3 weeks of each 4-week cycle.

The drug has a generally acceptable tolerability profile and does not compromise health-related quality of life, making it a valuable addition to treatment options for patients with progressive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Carter, NJ.[2021]

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Regorafenib alone or in combination with high/low-dose radiotherapy plus toripalimab as third-line treatment in patients with metastatic colorectal cancer: protocol for a prospective, randomized, controlled phase II clinical trial (SLOT). [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Ipilimumab as a Cause of Severe Pan-Colitis and Colonic Perforation. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Safety of Immune Checkpoint Inhibitors in Patients With Pre-Existing Inflammatory Bowel Disease and Microscopic Colitis. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Ipilimumab associated colitis: an IpiColitis case series at MedStar Georgetown University Hospital. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis. [2023]

11. Italy pubmed.ncbi.nlm.nih.gov

[Regorafenib in patients with metastatic colorectal cancer: a review and an update]. [2016]